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Colistin-induced acute kidney injury via zinc Dyshomeostasis-triggered GSDMD-executed Pyroptosis

Qinjie Yang1, Kun Liu1, Rongping Zhu1

  • 1Department of Pharmacy, The Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, China.

International Immunopharmacology
|November 2, 2025
PubMed

Insights

Colistin antibiotic use causes kidney injury by increasing cellular zinc and promoting programmed cell death (pyroptosis). Reducing zinc levels protected against this colistin-induced acute kidney injury (AKI).

Area of Science:

  • Nephrology
  • Toxicology
  • Cell Biology

Background:

  • Colistin is a last-line antibiotic for multidrug-resistant Gram-negative infections.
  • Colistin use is limited by nephrotoxicity, specifically acute kidney injury (AKI), with unknown mechanisms.
  • Pyroptosis, a programmed cell death pathway, is implicated in drug-induced AKI.

Purpose of the Study:

  • To investigate the role of pyroptosis in colistin-induced AKI.
  • To determine if zinc dyshomeostasis contributes to colistin-induced pyroptosis and AKI.

Main Methods:

  • Colistin sulfate was administered to mice and renal tubular epithelial cells.
  • Intracellular zinc levels and pyroptosis markers (GSDMD) were assessed.
  • The effect of zinc chelation on pyroptosis and renal damage was evaluated.

Main Results:

  • Colistin sulfate induced intracellular zinc overload in murine kidneys and renal tubular epithelial cells.
  • Zinc dyshomeostasis exacerbated gasdermin D (GSDMD)-executed pyroptosis.
  • Chelation of intracellular zinc attenuated pyroptosis and mitigated colistin-induced renal damage.

Conclusions:

  • Zinc dyshomeostasis-driven pyroptosis is a key pathogenic mechanism in colistin-associated nephrotoxicity.
  • Targeting intracellular zinc may offer a therapeutic strategy to prevent colistin-induced AKI.
Keywords:
Acute kidney injuryColistinPyroptosisZinc homeostasis

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